WO2017218569A2 - Peptides de liaison à l'intégrine alpha (v) bêta (6) et leurs procédés d'utilisation - Google Patents
Peptides de liaison à l'intégrine alpha (v) bêta (6) et leurs procédés d'utilisation Download PDFInfo
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- WO2017218569A2 WO2017218569A2 PCT/US2017/037303 US2017037303W WO2017218569A2 WO 2017218569 A2 WO2017218569 A2 WO 2017218569A2 US 2017037303 W US2017037303 W US 2017037303W WO 2017218569 A2 WO2017218569 A2 WO 2017218569A2
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- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
Definitions
- Integrins are a large family of cell-surface receptors responsible for mediating cell- cell and cell-extracellular matrix (ECM) adhesion. There are at least 24 different integrins, each a heterodimer composed of an a and ⁇ subunit, whose expression is determined by several factors including tissue type, stage of development, and various tissue pathologies such as inflammation and cancer. Although they do not possess any intrinsic enzymatic activity, subsequent to ligand binding, integrins translate extracellular cues into intracellular signals by bringing into juxtaposition a complex of cytoplasmic structural and signaling molecules that then interact and determine the cellular response. As integrins are involved in most elements of cell behavior including motility, proliferation, invasion, and survival, their roles in disease have been widely reported.
- integrins are thought to play an active role in promoting certain diseases including cancer.
- ⁇ ⁇ ⁇ 3 integrin has been implicated in promoting the invasive phenotype of melanoma and glioblastoma, owing to its multiple abilities including upregulating pro-invasive metalloproteinases as well as providing pro-migratory and survival signals.
- ⁇ ⁇ ⁇ 3 is also upregulated on endothelial cells of angiogenic blood vessels and may provide similar signals for the development of neo- vessels in cancer, such data have led many pharmaceutical and academic centers to develop antagonists of ⁇ ⁇ ⁇ 3 for therapeutic purposes, many of which have been peptides or peptidomimetics.
- understanding the structural basis of integrin-ligand interactions would aid in the design of improved integrin antagonists.
- the ⁇ ⁇ ⁇ 6 integrin receptor is expressed only on epithelial cells. This integrin is involved in both normal and pathological tissue processes. For example, ⁇ ⁇ ⁇ 6 is upregulated by epithelial cells during wound healing and inflammation. It is likely that the ability of ⁇ ⁇ ⁇ 6 to locally activate TGF- ⁇ by binding to its protective pro-peptide, the latency associated peptide (LAP), explains the function of this integrin in these transient pathologies. Thus, TGF- ⁇ can suppress inflammatory responses and epithelial proliferation, indicating that ⁇ ⁇ ⁇ 6 serves as a negative control to dampen-down these processes.
- LAP latency associated peptide
- Chronic inflammation can lead to an excess of a ⁇ 6 -dependent activation of TGF- ⁇ , resulting in fibrosis in the lung of experimental animals.
- some pathologies that result in fibrosis in humans may also involve a ⁇ 6 -dependent TGF- ⁇ activation.
- Constitutive ⁇ ⁇ ⁇ 6 overexpression in the skin of mice results in chronic wounds appearing on a significant number of transgenic animals.
- chronic wounds associated with human diseases e.g., certain forms of epidermolysis bullosa
- ⁇ ⁇ ⁇ 6 is a major target in cancer. Although ⁇ ⁇ ⁇ 6 is epithelial-specific, it is weak or undetectable in most resting epithelial tissues but is strongly upregulated in many types of cancer, often at the invasive front. For example, ⁇ ⁇ ⁇ 6 is highly upregulated in oral squamous cell carcinoma (OSCC), pancreatic cancer, ovarian cancer, and colon cancer. It has been shown that ⁇ ⁇ ⁇ 6 can promote carcinoma invasion by upregulating metalloproteinases and promoting increased motility such that survival of carcinoma cells is promoted by upregulation of Akt. These data indicate that ⁇ ⁇ ⁇ 6 actively promotes the invasive phenotype. It has also been shown that high expression of ⁇ ⁇ ⁇ 6 correlates with a significant reduction in median survival by colon cancer patients.
- OSCC oral squamous cell carcinoma
- Akt Akt
- the present invention provides a conjugate comprising a peptide that comprises the amino acid sequence VGDLTYLK (SEQ ID NO: l) and a moiety.
- the moiety is covalently attached to the peptide.
- the peptide is between about 8 and about 20 amino acids in length.
- the conjugate comprises one or more additional lysine residues.
- the one or more additional lysine residues are attached to the C- terminal end of the peptide and/or to one or more moieties.
- the conjugate comprises the amino acid sequence VGDLTYLKK (SEQ ID NO: 10) and a moiety.
- the peptide binds to an integrin.
- the integrin is ⁇ ⁇ ⁇ 6 integrin.
- the moiety is selected from the group consisting of a polyethylene glycol (PEG) moiety, a fluorobenzoyl (FB) group, a methyl group, an acetyl group, an imaging agent, a therapeutic agent, and a combination thereof.
- the PEG moiety has a molecular weight of less than about 3,000 daltons (Da).
- the PEG moiety is selected from the group consisting of PEG 12 (PEG 800), PEG 28 (PEG 1,500), and a combination thereof.
- the PEG moiety is a monodisperse PEG moiety having a defined chain length. In some instances, the monodisperse PEG moiety has greater than about 95% oligomer purity.
- the imaging agent is selected from the group consisting of an FB group, a radionuclide, biotin, a fluorophore, a fluorescent protein, an antibody, horseradish peroxidase, alkaline phosphatase, and a combination thereof.
- the radionuclide is selected from the group consisting of C, N, O, F, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, m In, 124 I, 125 I, and 131 I. In some instances, the radionuclide is 18 F. In some embodiments, the moiety is attached to the peptide, to the one or more additional lysine residues, and/or to another moiety.
- one additional lysine residue is attached to the C-terminal end of the peptide and an FB group is attached to the side chain of the additional lysine residue, such that the conjugate comprises the sequence VGDLTYLKK(FB) (SEQ ID NO:2).
- the conjugate further comprises an FB group that is attached to the N-terminal end of the peptide and a PEG 28 moiety that is attached to the C-terminal lysine residue, such that the conjugate comprises the sequence FB-VGDLTYLKK(FB)-PEG 28 (SEQ ID NO:3).
- the conjugate comprises the sequence (VGDLTYLK- PEGi 2 ) 2 KK(FB) (SEQ ID NO:4), wherein the conjugate comprises a dimer of the amino acid sequence VGDLTYLK (SEQ ID NO: l), wherein a PEG 12 moiety is attached to the C- terminal end of each member of the dimer, wherein both PEG 12 moieties are attached to the first of two additional lysine residues, and wherein an FB group is attached to the side chain of the second of the two additional lysine residues.
- FB groups are attached to the N-terminal ends of each peptide of the dimer, such that the conjugate comprises the sequence (FB-VGDLTYLK-PEGi 2 ) 2 KK(FB) (SEQ ID NO:5).
- the conjugate comprises the sequence (VGDLTYLK-PEGi 2 ) 2 KK(FB) (SEQ ID NO: 4), wherein the conjugate comprises a tetramer of the amino acid sequence VGDLTYLK (SEQ ID NO: l).
- the FB group that is attached to the lysine residue is radiolabeled with 18 F.
- the therapeutic agent is selected from the group consisting of a radionuclide, a pro-apoptotic peptide, a nanoparticle, a chemotherapeutic agent, a nanodroplet, a liposomal drug, a cytokine, and combinations thereof.
- the present invention provides a composition that comprises a conjugate described herein or a plurality thereof.
- a conjugate described herein or a plurality thereof monodisperse PEG moieties having a defined chain length are present in the plurality of conjugates.
- the composition further comprises a pharmaceutical carrier or excipient.
- the present invention provides a kit for imaging or therapy.
- the kit comprises a conjugate described herein or a composition described herein.
- the kit further comprises instructions for use.
- the kit further comprises one or more reagents.
- the present invention provides a method for imaging a target tissue in a subject.
- the method comprises administering to the subject a conjugate described herein or a composition described herein, wherein the conjugate comprises an imaging agent, and detecting the conjugate to determine where the conjugate is concentrated in the subject.
- the imaging agent is covalently attached to the peptide, an FB group, or a PEG moiety.
- the target tissue is a cancerous tissue or an organ.
- the cancerous tissue is associated with pancreatic cancer, breast cancer, colorectal cancer, prostate cancer, or oral squamous cell carcinoma.
- the imaging agent is a radionuclide.
- the radionuclide is covalently attached to an FB group.
- radiation from the radionuclide is used to determine where the conjugate is concentrated in the subject.
- the conjugate is detected for the diagnosis or prognosis of a disease or disorder mediated by an integrin.
- the disease or disorder is associated with the expression, overexpression, or activation of the integrin.
- the present invention provides a method for preventing of treating an integrin-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a conjugate described herein or a composition described herein, wherein the conjugate comprises a therapeutic agent.
- the therapeutic agent is covalently attached to the peptide or a PEG moiety.
- the disease or disorder is associated with the expression, overexpression, or activation of the integrin.
- the disease or disorder is selected from the group consisting of cancer, an inflammatory disease, an autoimmune disease, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, radiation-induced pulmonary fibrosis, and chronic wounding skin disease.
- the disease or disorder is an ⁇ ⁇ ⁇ 6 integrin-mediated disease or disorder.
- the ⁇ ⁇ ⁇ 6 integrin-mediated disease or disorder is pancreatic cancer, breast cancer, colorectal cancer, prostate cancer, or oral squamous cell carcinoma.
- the therapeutically effective amount of the conjugate or the composition is an amount sufficient to target delivery of the therapeutic agent to a cell expressing the integrin.
- FIG. 1 summarizes the creation of a one-bead one-compound (OBOC) fluorobenzoyl peptide library.
- OBOC one-bead one-compound
- FIGS. 2A and 2B show fluorescent cell-based on-bead screening.
- FIG. 2A shows a summary of the steps involved in fluorescent cell-based on-bead screening.
- FIG. 2B shows an on-bead two-color screening approach using mixed ⁇ 3 ⁇ 6 mCherry (a v P6-positive) and DX3 EmGFP (a v p 6 -negative) cell lines.
- FIG. 3 shows results of the on-bead screening, including Peptides 1-5 (SEQ ID NOS:2 and 6-9).
- FIG. 4 shows on-bead validation of the peptide hits (Peptides 1-5; SEQ ID NOS:2 and 6-9).
- FIGS. 5A and 5B show competitive binding ELISAs of peptides of the present invention.
- FIG. 5A shows various integrins and their natural ligands.
- FIG. 5B shows ELISA results of Peptides 1-5 (SEQ ID NOS:2 and 6-9).
- FIGS. 6A and 6B show solid-phase radiolabeling of peptides.
- FIG. 6A shows a schematic of the radiolabeling process.
- FIG. 6B shows the results of an assay of radiolabeling yield and purity.
- FIGS. 7A and 7B show serum stability studies.
- FIG. 7A shows the results of a serum stability study of Peptide 1 (ST1-62) (SEQ ID NO:2), in which the C-terminal fluorobenzoyl group was radiolabeled with 18 F.
- FIG. 7B shows the results of a serum stability study of a PEGylated peptide (ST 1-92) comprising the amino acid sequence set forth in SEQ ID NO:3, in which the C-terminal fluorobenzoyl group has been radiolabeled with
- FIGS. 8A and 8B show binding of a peptide labeled with FAM-X (VGDLTYLKK- FAM-X; SEQ ID NO: 15) to DX3purop6 and DX3 puro cells.
- FIG. 8A shows the results of binding studies that were conducted using three concentrations of the peptide (0.1, 1, and 10 ⁇ ). 150,000 cells were used in each experiment.
- FIG. 8B shows the results of binding studies that were conducted using a peptide concentration of 100 ⁇ . These studies used 75,000, 150,000, or 300,000 cells per experiment. The control experiment used 300,000 unstained cells.
- the present invention is based, in part, on the discovery of conjugates that were identified using a novel one-step on-bead screening approach using mixed fluorescent cells for the identification of integrin a v p 6 -targeting conjugates from a fluorobenzoyl one-bead one-compound (OBOC) peptide library.
- Five beads isolated from the assay were selected for sequencing, and binding specificities toward ⁇ ⁇ ⁇ 6 , ⁇ ⁇ ⁇ 3 , ⁇ ⁇ ⁇ 5 , ⁇ ⁇ ⁇ , and ⁇ ⁇ ⁇ 8 were evaluated using competitive binding ELISA.
- Conjugates that bound to ⁇ 6 integrin with high affinity and with high selectivity ratios were subsequently optimized and developed into 18 F- conjugates (i.e., conjugates comprising an F radionuclide attached to a fluorobenzoyl group) that are useful for noninvasive imaging via positron emission tomography (PET).
- F- conjugates i.e., conjugates comprising an F radionuclide attached to a fluorobenzoyl group
- conjugate is intended to include a chemical compound that has been formed by the joining or attachment of two or more compounds.
- a conjugate of the present invention comprises a peptide (e.g., an integrin-binding peptide) attached (e.g., covalently attached) to a moiety.
- the conjugate of the present invention can further comprise one or more additional amino acids (e.g., additional lysine residues), an imaging agent (e.g., a fluorobenzoyl group and/or a radionuclide such as 18 F), a therapeutic agent, or other moiety attached to the peptide, the one or more additional amino acids, and/or one or more moieties.
- integrin-binding peptide and "binds to an integrin” refer to the binding/interaction of a peptide motif in the conjugate which shows the capacity of specific interaction with a specific integrin or a specific group of integrins.
- the terms refer to the ability of a peptide or a portion thereof to interact with and/or bind to a target integrin and without cross-reacting with molecules of similar sequences or structures.
- a peptide specifically binds to a target integrin when it binds to the target integrin with a substantially lower dissociation constant (i.e., tighter binding) than a molecule of similar sequence or structure.
- a specific binding occurs when the peptide binds to the target integrin with an about 2, 3, 4, 5, 6, 8, 10, 15, 20, 25, 30, 40, 50, 100, or 1000-fold or greater affinity than a related molecule.
- the binding of the peptide to a site on the target integrin may occur via intermolecular forces such as ionic bonds, hydrogen bonds, hydrophobic interactions, dipole-dipole bonds, and/or Van der Waals forces.
- Cross-reactivity may be tested, for example, by assessing binding of the peptide under conventional conditions to the target integrin as well as to a number of more or less (e.g., structurally and/or functionally) closely related molecules.
- These methods may include, without limitation, binding studies, blocking and competition studies with closely related molecules, FACS analysis, surface plasmon resonance (e.g., with BIAcore), analytical ultracentrifugation, isothermal titration calorimetry, fluorescence anisotropy, fluorescence spectroscopy, radiolabeled ligand binding assays, and combinations thereof.
- amino acid includes naturally-occurring a-amino acids and their stereoisomers, as well as unnatural amino acids and their stereoisomers.
- “Stereoisomers” of amino acids refers to mirror image isomers of the amino acids, such as L-amino acids or D- amino acids.
- a stereoisomer of a naturally-occurring amino acid refers to the mirror image isomer of the naturally-occurring amino acid, i.e., the D-amino acid.
- Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., ⁇ -carboxyglutamate and 0-phosphoserine.
- Naturally-occurring a-amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (He), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gin), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof.
- Stereoisomers of a naturally-occurring a- amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-phenylalanine (D-Phe), D-histidine (D-His), D- isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D-Leu), D-methionine (D-Met), D-asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D-Gln), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D-tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof.
- D-Ala
- Unnatural amino acids include, without limitation, amino acid analogs, amino acid mimetics, synthetic amino acids, N-substituted glycines, and N-methyl amino acids in either the L- or D-configuration that function in a manner similar to the naturally-occurring amino acids.
- amino acid analogs are unnatural amino acids that have the same basic chemical structure as naturally-occurring amino acids, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, but have modified R ⁇ i.e., side-chain) groups.
- Non-limiting examples of unnatural amino acids include 1-aminocyclopentane-l- carboxylic acid (Acp), 1-aminocyclobutane- 1-carboxylic acid (Acb), 1-aminocyclopropane- 1-carboxylic acid (Acpc), citrulline (Cit), homocitrulline (HoCit), a-aminohexanedioic acid (Aad), 3-(4-pyridyl)alanine (4-Pal), 3-(3-pyridyl)alanine (3 -Pal), propargylglycine (Pra), a- aminoisobutyric acid (Aib), a-aminobutyric acid (Abu), norvaline (Nva), ⁇ , ⁇ - diaminopropionic acid (Dpr), ⁇ , ⁇ -diaminobutyric acid (Dbu), ⁇ -tert-butylglycine (Bug), 3,5- din
- amino acid mimetics are chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally-occurring amino acid.
- Suitable amino acid mimetics include, without limitation, ⁇ -amino acids and ⁇ -amino acids.
- ⁇ -amino acids the amino group is bonded to the ⁇ -carbon atom of the carboxyl group such that there are two carbon atoms between the amino and carboxyl groups.
- ⁇ -amino acids the amino group is bonded to the ⁇ -carbon atom of the carboxyl group such that there are three carbon atoms between the amino and carboxyl groups.
- Suitable R groups for ⁇ - or ⁇ -amino acids include, but are not limited to, side-chains present in naturally-occurring amino acids and unnatural amino acids.
- 'W-substituted glycines are unnatural amino acids based on glycine, where an amino acid side-chain is attached to the glycine nitrogen atom.
- Suitable amino acid side- chains include, but are not limited to, side chains present in naturally- occurring amino acids and side-chains present in unnatural amino acids such as amino acid analogs.
- Non-limiting examples of N-substituted glycines include N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-(2-methoxyethyl)glycine, N-benzylglycine, (S)-N-(l- phenylethyl)glycine, N-cyclohexylmethylglycine, N-(2-phenylethyl)glycine, N-(3- phenylpropyl)glycine, N-(6-aminogalactosyl)glycine, N-(2-(3'-indolylethyl)glycine, N-(2-(p- methoxyphenylethyl))glycine, N-(2-(p-chlorophenylethyl)glycine, and N-[2-(p- hydroxyphenylethyl)]glycine.
- N-substituted glycine oligomers referred to herein as "peptoids,” have been shown to be protease resistant (see, e.g., Miller et al, Drug Dev. Res., 35:20-32 (1995)).
- Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
- an L-amino acid may be represented herein by its commonly known three letter symbol (e.g., Arg for L-arginine) or by an upper-case one-letter amino acid symbol (e.g., R for L-arginine).
- a D-amino acid may be represented herein by its commonly known three letter symbol (e.g., D-Arg for D-arginine) or by a lower-case one- letter amino acid symbol (e.g., r for D-arginine).
- amino acid sequences With respect to amino acid sequences, one of skill in the art will recognize that individual substitutions, additions, or deletions to a peptide, polypeptide, or protein sequence which alters, adds, or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid.
- the chemically similar amino acid includes, without limitation, a naturally-occurring amino acid such as an L-amino acid, a stereoisomer of a naturally occurring amino acid such as a D-amino acid, and an unnatural amino acid such as an amino acid analog, amino acid mimetic, synthetic amino acid, N-substituted glycine, and N-methyl amino acid.
- a naturally-occurring amino acid such as an L-amino acid
- a stereoisomer of a naturally occurring amino acid such as a D-amino acid
- an unnatural amino acid such as an amino acid analog, amino acid mimetic, synthetic amino acid, N-substituted glycine, and N-methyl amino acid.
- amino acids e.g., G, A, I, L, or V
- an aliphatic polar-uncharged group such as C, S, T, M, N, or Q
- basic residues e.g., K, R, or H
- an amino acid with an acidic side chain e.g., E or D
- may be substituted with its uncharged counterpart e.g., Q or N, respectively; or vice versa.
- Each of the following eight groups contains other exemplary amino acids that are conservative substitutions for one another:
- peptide refers to a compound made up of a single chain of D- or L- amino acids or a mixture of D- and L-amino acids joined by peptide bonds. Generally, peptides are about 2 to about 50 amino acids in length. As non-limiting examples, the peptides (e.g., integrin-binding peptides) present in the conjugates described herein are about 5 to about 45 amino acids in length, about 8 to about 45 amino acids in length, about 8 to about 25 amino acids in length, about 8 to about 20 amino acids in length, about 12 to about 45 amino acids in length, about 12 to about 30 amino acids in length, about 8 amino acids in length, or about 20 amino acids in length.
- peptides e.g., integrin-binding peptides
- the N-terminal amine group of a peptide is considered to be free.
- the sequences NH 2 -VGD and VGD both denote a three-amino acid VGD peptide sequence having a free N-terminal amine group.
- the sequences NH 2 -VGD and VGD both denote peptides that can be protected on the N-terminal end with a fluorobenzoyl (FB) group to yield a conjugate having the sequence FB-VGD.
- FB fluorobenzoyl
- PEGylation refers to the process of covalently coupling a polyethylene glycol (PEG) molecule to another molecule, e.g., a peptide, polypeptide, protein, moiety, and the like, which is then referred to as "PEGylated.”
- PEG polyethylene glycol
- a therapeutically effective amount refers to the amount of a conjugate or composition of the present invention that is capable of achieving a therapeutic effect in a subject in need thereof.
- a therapeutically effective amount of a conjugate or composition of the present invention can be the amount that is capable of preventing or relieving one or more symptoms associated with a disease or disorder.
- conjugates and compositions of the present invention can be coadministered with other therapeutic agents such as anticancer, anti-inflammatory, immunosuppressive, antiviral, antibiotic, and/or antifungal agents.
- administering includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
- Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
- Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
- Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
- One skilled in the art will know of additional methods for administering a therapeutically effective amount of a conjugate or composition of the present invention for preventing or relieving one or more symptoms associated with a disease or disorder such as cancer or an inflammatory or autoimmune disease.
- conjugate or composition of the present invention is administered at the same time, just prior to, or just after the administration of a second drug (e.g., anticancer agent, anti-inflammatory agent, immunosuppressive agent, antiviral agent, antibiotic, antifungal agent, etc.).
- a second drug e.g., anticancer agent, anti-inflammatory agent, immunosuppressive agent, antiviral agent, antibiotic, antifungal agent, etc.
- radioactivity refers to the radiation, including alpha particles, beta particles, nucleons, electrons, positrons, neutrinos, and gamma rays, emitted by a radioactive substance.
- radionuclides suitable for use in the present invention include, but are not limited to, fluorine 18 ( 18 F), phosphorus 32 ( 32 P), scandium 47 ( 47 Sc), cobalt 55 ( 55 Co), copper 60 ( 60 Cu), copper 61 ( 61 Cu), copper 62 ( 62 Cu), copper 64 ( 64 Cu), gallium 66 ( 66 Ga), copper 67 ( 67 Cu), gallium 67 ( 67 Ga), gallium 68 ( 68 Ga), rubidium 82 ( 82 Rb), yttrium 86 ( 86 Y), yttrium 87 ( 87 Y), strontium 89 ( 89 Sr), yttrium 90 ( 90 Y), rhodium 105 ( 105 Rh), silver 111 ( lu Ag), indium 111 ( m In), iodine 124 ( 124 I), iodine 125 ( 125 I), iodine 131 ( 131 I), tin 117m ( 117m Sn), tech
- 67 " 131 1W represent mixtures of radioisotopes, are suitable examples of radionuclides.
- Cu, I, Lu, and 186 Re are beta- and gamma-emitting radionuclides.
- 212 Bi is an alpha- and beta-emitting radionuclide.
- 211 At is an alpha-emitting radionuclide.
- 32 P, 47 Sc, 89 Sr, 90 Y, 105 Rh, lu Ag, 117m Sn, 149 Pm, 153 Sm, 166 Ho, and 188 Re are examples of beta-emitting radionuclides.
- 67 Ga, lu In, 99m Tc, and 201 T1 are examples of gamma-emitting radionuclides.
- 60 Cu, 61 Cu, 62 Cu, 66 Ga, 68 Ga, 82 Rb, and 86 Y are examples of positron-emitting radionuclides.
- 64 Cu is a beta- and positron-emitting radionuclide.
- subject typically refers to humans, but can also include other animals such as, e.g., other primates, rodents, canines, felines, equines, ovines, porcines, and the like.
- the present invention provides conjugates and compositions that target an integrin such as ⁇ ⁇ ⁇ 6 integrin.
- the conjugates comprise a peptide comprising the amino acid sequence VGDLTYLK (SEQ ID NO: l) and a moiety. The moiety, or a plurality thereof, can be covalently or noncovalently attached to the peptide.
- the conjugates further comprise one or more additional amino acid residues.
- the conjugates further comprise one or more additional lysine residues.
- the one or more additional amino acid residues can be attached anywhere on the peptide (e.g., the N-terminal end of the peptide, the C-terminal end of the peptide and/or to one or more moieties.
- the one more amino acid residues are attached to the C-terminal end and/or one or more moieties.
- the conjugates comprise the amino acid sequence VGDLTYLKK (SEQ ID NO: 10) and a moiety.
- the moiety is selected from the group consisting of a polyethylene glycol (PEG) moiety, a fluorobenzoyl (FB) group (e.g., an FB group that is not radiolabeled), a methyl group, an acetyl group, an imaging agent described herein (e.g., an FB group and/or a radionuclide (e.g., 18 F)), a therapeutic agent described herein (e.g., a radionuclide, a pro-apoptotic peptide, a nanoparticle, a chemotherapeutic agent, a nanodroplet, a liposomal drug, a cytokine, and combinations thereof), and a combination thereof.
- PEG polyethylene glycol
- FB fluorobenzoyl
- a therapeutic agent described herein e.g., a radionuclide, a pro-apoptotic peptide, a nanoparticle, a chemotherapeutic agent, a nano
- the FB group When an FB group is used as an imaging agent, in some instances the FB group will be radiolabeled (e.g., have a radionuclide covalently attached to it).
- the moiety can be covalently or noncovalently attached to the peptide, to one or more amino acid residues (e.g., lysine residues), and/or to another moiety.
- the conjugate further comprises an albumin binding motif that is covalently attached to the peptide or a PEG moiety. In some instances, the albumin binding motif is 4-(4-iodophenyl)butyric acid.
- each PEG moiety has a different size or molecular weight. In other instances, all of the PEG moieties in a conjugate are of the same size or molecular weight. In some embodiments, the PEG moiety has a molecular weight of less than about 5,000 daltons (Da). In particular embodiments, the PEG moiety has a molecular weight of less than about 3,000 daltons (Da). In preferred embodiments, the PEG moiety is a monodisperse PEG moiety having a defined chain length.
- PEG moieties having a defined chain length generally include PEG molecules of discrete molecular weights with an exactly defined number of repeating ethylene glycol units.
- Non-limiting examples of PEG moieties having a defined chain length include small, monodisperse PEG molecules having greater than about 90%, 91%, 92%, 93%, 94%, or 95% oligomer purity.
- PEG compound mixtures having an average molecular weight are not used in the conjugates of the present invention.
- the PEG moiety is selected from the group consisting of PEGn, PEG 12 (PEG 800), PEG 28 (PEG 1,500), and (PEG 28 ) 2 (PEG 1,500x2).
- PEG units suitable for use in the conjugates of the present invention include PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 900, PEG 1,000, PEG 1, 100, PEG 1,200, PEG 1,300, PEG 1,400, PEG 1,600, PEG 1,700, PEG 1,800, PEG 1,900, PEG 2,000, PEG 2, 100, PEG 2,200, PEG 2,300, PEG 2,400, PEG 2,500, PEG 2,600, PEG 2,700, PEG 2,800, PEG 2,900, PEG 3,000, PEG 3,250, PEG 3,350, PEG 3,500, PEG 3,750, PEG 4,000, PEG 4,250, PEG 4,500, PEG 4,750, and PEG 5,000, as well as
- these PEG molecules contain an exactly defined number of repeating units "n" and are monodisperse (e.g., having greater than about 95% oligomer purity).
- PEG moieties suitable for use in the present invention are commercially available from EMD Chemicals, Inc. (San Diego, CA) and Polypure AS (Oslo, Norway).
- an additional lysine residue is attached (e.g., covalently attached) to the C-terminal end of the peptide.
- a fluorobenzoyl (FB) group is attached to the side chain of the additional lysine residue.
- the conjugate comprises the sequence VGDLTYLKK(FB) (SEQ ID NO:2).
- the FB group of the conjugate set forth in SEQ ID NO:2 is radiolabeled.
- the FB group is radiolabeled with 18 F.
- a moiety e.g., an FB group or a PEG moiety (e.g., PEG 28 )
- a moiety is attached (e.g., covalently attached) to the N-terminal end of the peptide.
- the conjugate set forth in SEQ ID NO:2 further comprises an FB group that is attached to the N-terminal end of the peptide.
- the conjugate set forth in SEQ ID NO:2 further comprises a PEG 28 group that is attached to the C-terminal lysine residue.
- the conjugate set forth in SEQ ID NO:2 further comprises an FB group that is attached to the N-terminal end of the peptide and a PEG 28 group that is attached to the C-terminal lysine residue, such that the conjugate has the sequence FB - VGDLT YLKK(FB )-PEG 28 (SEQ ID NO:3).
- the N-terminal FB group and/or the FB group attached to the lysine residue can be radiolabeled (e.g., with 18 F).
- Conjugates of the present invention can have linear or branched structures.
- the conjugate comprises a multimer (e.g., a dimer or tetramer) of a peptide sequence described herein (e.g., an amino acid sequence set forth in SEQ ID NO: 1 or 10).
- a conjugate can comprise the sequence (VGDLTYLK- PEGi 2 ) 2 KK(FB) (SEQ ID NO: 4), wherein the conjugate comprises a dimer of the amino acid sequence VGDLTYLK (SEQ ID NO: l), wherein a PEG 12 moiety is attached to the C- terminal end of each member of the dimer, wherein both PEG 12 moieties are attached to the first of two additional lysine residues, and wherein an FB group is attached to the side chain of the second of the two additional lysine residues.
- the conjugate set forth in SEQ ID NO:4 can further comprise FB groups that are attached to the N-terminal ends of each peptide of the dimer, such that the conjugate comprises the sequence (FB-VGDLTYLK-PEGi 2 ) 2 KK(FB) (SEQ ID NO:5).
- One or both of the N-terminal FB groups and/or the FB group attached to the lysine residue can be radiolabeled (e.g., with 18 F).
- the FB group attached to the lysine residue of the conjugate set forth in SEQ ID NO:4 or 5 is radiolabeled (e.g., with 18 F).
- the present invention provides conjugates that comprise a peptide of SEQ ID NOS: l l, 12, 13, or 14 and any moiety described herein.
- the peptides comprise the sequence set forth in SEQ ID NOS:6, 7, 8, or 9.
- the present invention also provides compositions comprising a conjugate described herein or a plurality thereof.
- monodisperse PEG moieties having a defined chain length are present in the plurality of conjugates within the compositions.
- the plurality of conjugates within the compositions are linked to each other to form a multimeric conjugate.
- the multimeric conjugate can be, for example, a dimer or a tetramer of the plurality of conjugates.
- the compositions further comprise a pharmaceutical carrier or excipient described herein.
- the present invention provides conjugates comprising peptides.
- the peptides are integrin-binding peptides.
- the integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. Integrins are transmembrane ⁇ heterodimers and at least 18 a and eight ⁇ subunits are known in humans, generating 24 heterodimers. The a and ⁇ subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer.
- Non-limiting examples of integrins include ⁇ , 2 ⁇ , ⁇ 3 ⁇ , ⁇ 4 ⁇ , ⁇ 5 ⁇ , ⁇ 6 ⁇ , ⁇ 7 ⁇ , ⁇ 8 ⁇ , ⁇ 9 ⁇ , ⁇ , ⁇ , ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ 3 , ⁇ ⁇ ⁇ 5 , ⁇ ⁇ ⁇ 6 , ⁇ ⁇ ⁇ 8 , ⁇ , ⁇ 3 , ⁇ 4 ⁇ 7 , ⁇ 3 ⁇ 4 ⁇ 7 , 6 ⁇ 4 , 3 ⁇ 4 2 , (3 ⁇ 4y$2, ⁇ 3 ⁇ 4 ⁇ 2 , ⁇ 2 , and combinations thereof.
- the integrin is ⁇ ⁇ ⁇ 3 integrin, ⁇ 3 ⁇ 4 ⁇ 3 integrin, or ⁇ ⁇ ⁇ 6 integrin.
- the peptide binds to (e.g., targets) ⁇ ⁇ ⁇ 6 integrin.
- the ⁇ ⁇ ⁇ 6 integrin-binding peptide comprises an amino acid sequence selected from the group consisting of VGDLTYLK (SEQ ID NO: l), VGDLTYLKK (SEQ ID NO: 10), RGDLMKLAK (SEQ ID NO: 11), RGDLADLRK (SEQ ID NO: 12), GIDLTSLTK (SEQ ID NO: 13), and RGDLRELAK (SEQ ID NO: 14).
- ⁇ ⁇ ⁇ 6 integrin which is a receptor for fibronectin, tenascin, vitronectin, the latency associated peptide (LAP) of TGF- ⁇ , and viral capsid protein (VPl) of foot-and-mouth disease virus (FMDV), is expressed at very low or undetectable levels in only a subset of epithelial cells in normal adult tissues (Breuss et al, J. Cell Set, 108:2241-2251 (1995)). However, ⁇ ⁇ ⁇ 6 integrin expression is increased dramatically during development, following injury or inflammation, or in a variety of epithelial neoplasms.
- keratinocytes show de novo expression of ⁇ ⁇ ⁇ 6 integrin in both oral and skin wounds (Breuss et al, supra; Clark et al., Am. J. Path., 148: 1407-1421 (1996)).
- ⁇ ⁇ ⁇ 6 integrin plays an active role in tumor invasion because its expression is often higher at the invasive margins of oral squamous cell carcinomas.
- ⁇ ⁇ ⁇ 6 integrin is an excellent target for both imaging and therapy of diseases or disorders such as pancreatic cancer, oral cancer, ovarian cancer, breast cancer, and colon cancer.
- PEGylation of ⁇ ⁇ ⁇ 6 integrin-binding peptides with small, monodisperse PEG molecules having a defined chain length ⁇ e.g., PEG 28 ) and/or attachment of moieties such as acetyl groups and fluorobenzoyl groups can be used to generate conjugates of the present invention that display significantly better localizing and/or targeting potential by providing high tumor selectivity and specificity for
- the peptide is a bivalent peptide that binds to the integrin and a receptor that is co-expressed with the integrin.
- co-expressed receptors include CXCR4.
- the bivalent peptide binds to both ⁇ ⁇ ⁇ 6 integrin and CXCR4.
- the receptor that is co-expressed with the integrin is another integrin.
- the peptide comprises a first peptide fragment that binds to an integrin linked to a second peptide fragment that binds to a co- expressed receptor.
- the peptide comprises a first peptide fragment that binds to a co-expressed receptor linked to a second peptide fragment that binds to an integrin.
- the first and second peptide fragments can be linked directly to each other or can be linked via a glycine linker or other suitable linker known in the art.
- the conjugates of the invention comprise a peptide that is about 5 to about 45 amino acids in length, about 8 to about 45 amino acids in length, about 8 to about 20 amino acids in length, about 12 to about 45 amino acids in length, about 5 to about 40 amino acids in length, about 10 to about 40 amino acids in length, or about 35, 30, 25, 20, 15, or 10 amino acids in length.
- the peptide may be about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or more amino acids in length.
- the peptide should not exceed a length which would allow the formation of a tertiary structure, such as, for example, greater than 45 amino acids if present as an isolated molecule.
- the peptide may exceed 45 amino acids if fused to a larger molecule such as an antibody or another protein or macromolecule which could prevent the formation of a tertiary structure within the peptide.
- the peptide may also exceed 45 amino acids if it is a multimeric peptide (e.g., a dimer having first and second peptide fragments).
- the peptide is about 8 or 9 amino acids in length.
- the peptides used in the conjugates of the invention can also be functional variants of the peptides as defined above, including peptides that possess at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more sequence identity with the peptides described above.
- the peptides can comprise naturally-occurring amino acids and/or unnatural amino acids.
- unnatural amino acids include, but are not limited to, D-amino acids, ornithine, diaminobutyric acid ornithine, norleucine ornithine, pyriylalanine, thienylalanine, naphthylalanine, phenylglycine, alpha and alpha-di substituted amino acids, N-alkyl amino acids, lactic acid, halide derivatives of naturally-occurring amino acids (e.g., trifluorotyrosine, p-Cl- phenylalanine, p-Br-phenylalanine, p-I-phenylalanine, etc.), L-allyl-glycine, b-alanine, L-a-amino butyric acid, L-g-amino butyric acid, L-a-amino isobutyric acid, L-e-amino caproic acid, 7-amino heptanoic acid, L me
- the peptides may be further modified.
- one or more amide bonds may be replaced by ester or alkyl backbone bonds.
- the peptides used in the conjugates of the invention may include both modified peptides and synthetic peptide analogues.
- Peptides may be modified to improve formulation and storage properties, or to protect labile peptide bonds by incorporating non-peptidic structures.
- Peptides of the present invention may be prepared using methods known in the art. For example, peptides may be produced by chemical synthesis, e.g., using solid phase techniques and/or automated peptide synthesizers, or by recombinant means. In certain instances, peptides may be synthesized using solid phase strategies on an automated multiple peptide synthesizer (Abimed AMS 422) using 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry.
- the peptides can then be purified by reversed phase-HPLC and lyophilized.
- the peptides may alternatively be prepared by cleavage of a longer peptide or full-length protein sequence.
- the peptides are built manually (e.g., on Nova Syn TGR resin using Fmoc chemistry).
- the peptide component of the conjugates of the invention may be cyclized.
- Methods are well known in the art for introducing cyclic structures into peptides to select and provide conformational constraints to the structure that result in enhanced stability.
- a C- or N-terminal cysteine can be added to the peptide, so that when oxidized the peptide will contain a disulfide bond, generating a cyclic peptide.
- Other peptide cyclization methods include the formation of thioethers and carboxyl- and amino- terminal amides and esters.
- Conjugates of the present invention e.g., comprising a peptide that comprises the amino acid sequence set forth in SEQ ID NO: 1 and a moiety
- compositions of the present invention e.g., comprising conjugates of the present invention or a plurality thereof
- the conjugates and compositions can be used for imaging organs and cancerous tissue.
- Non-limiting examples of suitable tumors include malignant tumors of the pancreas (e.g., adenocarcinomas, serous cystadenomas, acinar cell cancers, pancreatic neuroendocrine tumors such as insulinomas, etc.), breast, colon, rectum, prostate, head and neck (e.g., oral squamous cell carcinoma), or any other tissue or organ.
- malignant tumors of the pancreas e.g., adenocarcinomas, serous cystadenomas, acinar cell cancers, pancreatic neuroendocrine tumors such as insulinomas, etc.
- breast, colon, rectum, prostate, head and neck e.g., oral squamous cell carcinoma
- the conjugates and compositions are also useful for treating diseases and disorders such as cancer (e.g., pancreatic cancer, breast cancer, colon cancer, cervical cancer, lung cancer, etc.), inflammatory disease, autoimmune disease, chronic fibrosis, chrome obstructive pulmonary disease (COPD), lung emphysema, radiation-induced pulmonary fibrosis, and chronic wounding skin disease.
- cancer e.g., pancreatic cancer, breast cancer, colon cancer, cervical cancer, lung cancer, etc.
- COPD chrome obstructive pulmonary disease
- lung emphysema chronic fibrosis
- radiation-induced pulmonary fibrosis e.g., radiation-induced pulmonary fibrosis
- chronic wounding skin disease e.g., chronic wounding skin disease.
- the conjugates are useful for imaging, treating, diagnosing, and prognosticating diseases or disorders that are mediated by an integrin (e.g., ⁇ ⁇ ⁇ 6 integrin).
- administration can be, for example, intravenous, topical, subcutaneous, transcutaneous, transdermal, intramuscular, oral, intra-joint, parenteral, intra- arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, or by inhalation.
- administration may be directly to the tumor and/or into tissues surrounding the tumor.
- compositions comprising a plurality of conjugates of the present invention, or a plurality thereof, are administered.
- the plurality of conjugates comprise a combination of different conjugates.
- Conjugates and compositions of the present invention may be administered repeatedly, e.g., at least 2, 3, 4, 5, 6, 7, 8, or more times, or may be administered by continuous infusion.
- Suitable sites of administration include, but are not limited to, dermal, mucosal, bronchial, gastrointestinal, anal, vaginal, eye, and ear.
- the formulations may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, lozenges, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, gels, aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals (e.g., dogs), each unit containing a predetermined quantity of active material calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule).
- a suitable pharmaceutical excipient e.g., an ampoule
- more concentrated compositions may be prepared, from which the more dilute unit dosage compositions may then be produced.
- the more concentrated compositions thus will contain substantially more than, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times the amount of a conjugate or a plurality or combination of conjugates.
- compositions to be administered contains a quantity of the conjugate or plurality of conjugates in a pharmaceutically effective amount for imaging a tumor, organ, or tissue or for relief of a condition being treated, when administered in accordance with the teachings of this invention.
- salts of the conjugates of the present invention may be prepared and included in the compositions using standard procedures known to those skilled in the art of synthetic organic chemistry and described, e.g., by March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed., New York, Wiley-Interscience (1992).
- the compositions of the present invention include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like.
- the composition will contain about 0.01% to about 90%, about 0.1% to about 75%), about 0.1%> to 50%, or about 0.1% to 10% by weight of a conjugate of the present invention or a plurality thereof, with the remainder consisting of suitable pharmaceutical carrier and/or excipients.
- Appropriate excipients can be tailored to the particular composition and route of administration by methods well known in the art. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, supra.
- excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols, e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc.
- Carbopols e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc.
- compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens); pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; coloring agents; and flavoring agents.
- lubricating agents such as talc, magnesium stearate, and mineral oil
- wetting agents such as talc, magnesium stearate, and mineral oil
- emulsifying agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates (i.e., the parabens)
- pH adjusting agents such as inorganic and organic acids and bases
- sweetening agents coloring agents
- flavoring agents such as inorganic and organic acids and bases.
- the compositions may also comprise biodegradable polymer beads, dextran, and
- compositions can be in the form of tablets, lozenges, capsules, emulsions, suspensions, solutions, syrups, sprays, powders, and sustained-release formulations.
- Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
- the compositions take the form of a pill, tablet, or capsule, and thus, the composition can contain, along with the conjugate or plurality or combination of conjugates, any of the following: a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
- the compositions can also be formulated into a suppository disposed, for example, in a polyethylene glycol (PEG) carrier.
- PEG polyethylene glycol
- Liquid compositions can be prepared by dissolving or dispersing a conjugate or a plurality or combination of conjugates and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
- a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like.
- a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol, and the like.
- aqueous saline e.g.
- compositions of the present invention can be in the form of emulsions, lotions, gels, creams, jellies, solutions, suspensions, ointments, and transdermal patches.
- the composition can be delivered as a dry powder or in liquid form via a nebulizer.
- the compositions can be in the form of sterile injectable solutions and sterile packaged powders.
- injectable solutions are formulated at a pH of about 4.5 to about 7.5.
- compositions of the present invention can also be provided in a lyophilized form.
- Such compositions may include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer may be included in the lyophilized composition for reconstitution with, e.g., water.
- the lyophilized composition may further comprise a suitable vasoconstrictor, e.g., epinephrine.
- the lyophilized composition can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted composition can be immediately administered to a patient.
- administered dosages will be effective to deliver picomolar to micromolar concentrations of the conjugate or plurality or combination thereof to the appropriate site or sites.
- dose administered will vary depending on a number of factors, including, but not limited to, the particular conjugate or set of conjugates to be administered, the mode of administration, the type of application (e.g., imaging, diagnostic, prognostic, therapeutic, etc.), the age of the patient, and the physical condition of the patient.
- the smallest dose and concentration required to produce the desired result should be used.
- Dosage should be appropriately adjusted for children, the elderly, debilitated patients, and patients with cardiac and/or liver disease. Further guidance can be obtained from studies known in the art using experimental animal models for evaluating dosage.
- the increased metabolic stability, tumor retention, and tumor to blood ratios associated with the conjugates of the present invention permits a wider margin of safety for dosage concentrations and for repeated dosing.
- Conjugates of the present invention e.g., comprising a peptide that comprises the amino acid sequence set forth in SEQ ID NO: 1 and a moiety
- compositions of the present invention e.g., comprising conjugates of the present invention or a plurality thereof
- optical imaging agents e.g., radiotracers or imaging probes
- imaging of tumors tomographic imaging of organs, monitoring of organ functions, coronary angiography, fluorescence endoscopy, laser guided surgery, photoacoustic and sonofluorescence methods, and the like.
- the conjugates and compositions of the present invention are useful for the detection of the presence of tumors and other abnormalities by monitoring where a particular conjugate is concentrated in a subject.
- the conjugates and compositions are useful for laser-assisted guided surgery for the detection of micro-metastases of tumors upon laparoscopy.
- the conjugates and compositions are useful in the diagnosis of atherosclerotic plaques and blood clots.
- the conjugates and compositions of the present invention are useful in the imaging of: (1) ocular diseases in ophthalmology, e.g., to enhance the visualization of chorioretinal diseases such as vascular disorders, retinopathies, neovascularization, and tumors via direct microscopic imaging; (2) skin diseases such as skin tumors via direct microscopic imaging; (3) gastrointestinal, oral, bronchial, cervical, and urinary diseases and tumors via endoscopy; (4) atherosclerotic plaques and other vascular abnormalities via flexible endoscopic catheters; and (5) pancreatic tumors, breast tumors, brain tumors, perfusion, and stroke via 2D- or 3D-image reconstruction.
- ocular diseases in ophthalmology e.g., to enhance the visualization of chorioretinal diseases such as vascular disorders, retinopathies, neovascularization, and tumors via direct microscopic imaging
- skin diseases such as skin tumors via direct microscopic imaging
- conjugates or compositions of the present invention are used for both imaging and therapeutic applications.
- the imaging methods described herein can further comprise administering a therapeutic conjugate (i.e., a conjugate comprising a therapeutic agent) to a subject (e.g., in whom target tissue or organ is being imaged).
- a therapeutic conjugate i.e., a conjugate comprising a therapeutic agent
- an imaging conjugate i.e., a conjugate comprising an imaging agent
- a therapeutic conjugate that is different from the imaging conjugate are used (e.g., administered to the subject).
- different imaging and therapeutic conjugates are used, they can be present in a single composition, or can be present in different compositions, which in some instances may be co-administered.
- a conjugate of the present invention can comprise a radionuclide that is capable of being detected (e.g., for the purpose of imaging) and is also capable of delivering a desired therapy (e.g., to a target cell, tissue, or organ).
- the conjugates and compositions of the present invention can be administered either systemically or locally to the tumor, organ, or tissue to be imaged, prior to the imaging procedure.
- the conjugates and compositions are administered in doses effective to achieve the desired optical image of a tumor, tissue, or organ. Such doses may vary widely, depending upon the particular conjugate employed, the tumor, tissue, or organ subjected to the imaging procedure, the imaging equipment being used, and the like.
- the conjugates and compositions described herein are used to directly stain or label a sample so that the sample can be identified or quantitated.
- a specific conjugate can be added as part of an assay for a biological target analyte (e.g., antigen), as a detectable tracer element in a biological or non-biological fluid, or for other in vitro purposes known to one of skill in the art.
- a biological target analyte e.g., antigen
- the sample is obtained directly from a liquid source or as a wash from a solid material (organic or inorganic) or a growth medium in which cells have been introduced for culturing, or a buffer solution in which cells have been placed for evaluation.
- the cells are optionally single cells, including microorganisms, or multiple cells associated with other cells in two or three dimensional layers, including multicellular organisms, embryos, tissues, biopsies, filaments, biofilms, and the like.
- a detectable response generally refers to a change in, or occurrence of, an optical signal that is detectable either by observation or instrumentally.
- the detectable response is radioactivity (i.e., radiation), including alpha particles, beta particles, nucleons, electrons, positrons, neutrinos, and gamma rays emitted by a radioactive substance such as a radionuclide.
- the detectable response is fluorescence or a change in fluorescence, e.g., a change in fluorescence intensity, fluorescence excitation or emission wavelength distribution, fluorescence lifetime, and/or fluorescence polarization.
- a standard or control e.g., healthy tissue or organ.
- the conjugates of the present invention typically have an imaging agent covalently or noncovalently attached to one or more of the peptide (e.g., comprising the amino acid sequence set forth in SEQ ID NO: l), one or more additional amino acid residues (e.g., lysine residues), or another moiety.
- the imaging agent is covalently or noncovalently attached to the peptide.
- the imaging agent is covalently or noncovalently attached to another imaging agent (e.g., a fluorobenzoyl (FB) group).
- FB fluorobenzoyl
- the imaging agent is covalently or noncovalently attached to a PEG moiety (e.g., PEG 12 (PEG 800), PEG 28 (PEG 1,500), or a combination thereof).
- Suitable imaging agents include, but are not limited to, FB groups, radionuclides, detectable tags, fluorophores, fluorescent proteins, enzymatic proteins, and the like.
- the imaging agent is an FB group or a radionuclide (e.g., 18 F).
- the imaging agent comprises a combination of an FB group and a radionuclide (e.g., a radionuclide (e.g., 18 F) covalently attached to the FB group).
- the imaging agent e.g., fluorobenzoyl group
- the imaging agent can be directly attached to the peptide, one or more additional amino acids (e.g., lysine residues) or a moiety (e.g., PEG moiety) of the conjugate via covalent attachment of the imaging agent to a primary amine group present in the peptide or PEG moiety.
- an imaging agent e.g., FB group
- FB group can be attached to the side chain of a lysine residue.
- an imaging agent e.g., FB group
- an imaging agent can also be bound to the peptide, one or more additional amino acids (e.g., lysine residues) or a moiety (e.g., PEG moiety) of the conjugate via noncovalent interactions (e.g., ionic bonds, hydrophobic interactions, hydrogen bonds, Van der Waals forces, dipole-dipole bonds, etc.).
- radiolabel the conjugates of the present invention.
- the radionuclide is bound to a chelating agent or chelating agent-linker attached to the conjugate.
- radionuclides for direct conjugation include, without limitation, F, I, I, I, and mixtures thereof.
- Suitable radionuclides for use with a chelating agent include, without limitation, 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, 212 Bi, and mixtures thereof.
- Additional radionuclides suitable for use in conjugates of the present invention include U C, 13 N, 15 0, 61 Cu, 62 Cu, and 68 Ga.
- the radionuclide is 18 F.
- Suitable chelating agents include, but are not limited to, DOTA, NOTA, NOTA-TCO, BAD, TETA, DTP A, EDTA, NTA, HDTA, their phosphonate analogs, and mixtures thereof.
- attachment can be conveniently accomplished using, for example, commercially available bifunctional linking groups (generally heterobifunctional linking groups) that can be attached to a functional group present in a non-interfering position on the conjugate and then further linked to a radionuclide, chelating agent, or chelating agent-linker.
- bifunctional linking groups generally heterobifunctional linking groups
- Non-limiting examples of fluorophores or fluorescent dyes suitable for use as imaging agents include Alexa Fluor ® dyes (Invitrogen Corp.; Carlsbad, CA), fluorescein, fluorescein isothiocyanate (FITC), Oregon GreenTM; rhodamine, Texas red, tetrarhodamine isothiocynate (TRITC), CyDyeTM fluors (e.g., Cy2, Cy3, Cy5), and the like.
- fluorescent proteins suitable for use as imaging agents include, but are not limited to, green fluorescent protein, red fluorescent protein (e.g., DsRed), yellow fluorescent protein, cyan fluorescent protein, blue fluorescent protein, and variants thereof (see, e.g., U.S. Patent Nos. 6,403,374, 6,800,733, and 7, 157,566).
- GFP variants include, but are not limited to, enhanced GFP (EGFP), destabilized EGFP, the GFP variants described in Doan et al, Mol. Microbiol, 55: 1767-1781 (2005), the GFP variant described in Crameri et al, Nat.
- DsRed variants are described in, e.g., Wang et al, Proc. Natl. Acad. Sci. U.S.A., 101 : 16745-16749 (2004) and include mRaspbeny and mPlum. Further examples of DsRed variants include mRFPmars described in Fischer et al, FEBS Lett., 577:227-232 (2004) and mRFPruby described in Fischer et al, FEBS Lett., 580:2495- 2502 (2006).
- the imaging agent that is bound to a conjugate of the present invention comprises an antibody or a detectable tag such as, for example, biotin, avidin, streptavidin, or neutravidin.
- the imaging agent comprises an enzymatic protein including, but not limited to, luciferase, chloramphenicol acetyltransferase, ⁇ -galactosidase, ⁇ -glucuronidase, horseradish peroxidase, xylanase, alkaline phosphatase, and the like.
- any device or method known in the art for detecting the radioactive emissions of radionuclides in a subject is suitable for use in the present invention.
- methods such as Single Photon Emission Computerized Tomography (SPECT), which detects the radiation from a single photon gamma-emitting radionuclide using a rotating gamma camera, and radionuclide scintigraphy, which obtains an image or series of sequential images of the distribution of a radionuclide in tissues, organs, or body systems using a scintillation gamma camera, may be used for detecting the radiation emitted from a radiolabeled conjugate of the present invention.
- SPECT Single Photon Emission Computerized Tomography
- radionuclide scintigraphy which obtains an image or series of sequential images of the distribution of a radionuclide in tissues, organs, or body systems using a scintillation gamma camera
- Positron emission tomography is another suitable technique for detecting radiation in a subject.
- U.S. Patent No. 5,429,133 describes a laparoscopic probe for detecting radiation concentrated in solid tissue tumors.
- Miniature and flexible radiation detectors intended for medical use are produced by Intra-Medical LLC (Santa Monica, CA).
- Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), or any other imaging technique known to one of skill in the art is also suitable for detecting the radioactive emissions of radionuclides.
- MRI Magnetic Resonance Imaging
- MRS Magnetic Resonance Spectroscopy
- radiation from a radionuclide is used to determine where the conjugate or composition is concentrated in a subject. Regardless of the method or device used, such detection is aimed at determining where the conjugate is concentrated in a subject, with such concentration being an indicator of the location of a tumor or tumor cells.
- Non-invasive fluorescence imaging of animals and humans can also provide in vivo diagnostic or prognostic information and be used in a wide variety of clinical specialties. For instance, techniques have been developed over the years for simple ocular observations following UV excitation to sophisticated spectroscopic imaging using advanced equipment ⁇ see, e.g., Andersson-Engels et al, Phys. Med. Biol., 42:815-824 (1997)). Specific devices or methods known in the art for the in vivo detection of fluorescence, e.g., from fluorophores or fluorescent proteins, include, but are not limited to, in vivo near-infrared fluorescence (see, e.g., Frangioni, Curr. Opin. Chem.
- Other methods or devices for detecting an optical response include, without limitation, visual inspection, CCD cameras, video cameras, photographic film, laser-scanning devices, fluorometers, photodiodes, quantum counters, epifluorescence microscopes, scanning microscopes, flow cytometers, fluorescence microplate readers, and signal amplification using photomultiplier tubes.
- Conjugates of the present invention e.g., comprising a peptide that comprises the amino acid sequence set forth in SEQ ID NO: 1 and a moiety
- compositions of the present invention e.g., comprising conjugates of the present invention or a plurality thereof
- the methods of prevention or treatment comprise administering a therapeutically effective amount of a conjugate or composition of the present invention, wherein the conjugate comprises a therapeutic agent.
- the therapeutically effective amount of a conjugate or composition is an amount sufficient to target delivery of the therapeutic agent to a cell expressing an integrin (e.g., ⁇ ⁇ ⁇ 6 integrin).
- integrin e.g., ⁇ ⁇ ⁇ 6 integrin.
- Conjugates and compositions of the present invention are particularly useful for treating diseases and disorders that are associated with the expression, overexpression, or activation of an integrin (e.g., ⁇ ⁇ ⁇ 6 integrin).
- diseases or disorders suitable for treatment with the conjugates and compositions described herein include, but are not limited to, allergy, anxiety disorder, autoimmune disease, behavioral disorder, birth defect, blood disorder, bone disease, cancer, chronic fibrosis, chronic obstructive pulmonary disease (CQPD), chronic wounding skin disease, circulatory disease, tooth disease, depressive disorder, dissociative disorder, ear condition, eating disorder, eye condition, food allergy, food-borne illness, gastrointestinal disease, genetic disorder, heart disease, hormonal disorder, immune deficiency, infectious disease, inflammatory disease, insect-transmitted disease, nutritional disorder, kidney disease, leukodystrophy, liver disease, lung emphysema, mental health disorder, metabolic disease, mood disorder, musculodegenerative disorder, neurological disorder, neurodegenerative disorder, neuromuscular disorder, personality disorder, phobia, pregnancy complication, prion disease, prostate disease, psychological disorder, psychiatric disorder, respiratory disease, sexual disorder, skin condition, sleep disorder, speech-language disorder, sports injury, tropical disease, vestibular disorder,
- the ⁇ ⁇ ⁇ 6 - mediated disease or disorder is cancer, an inflammatory disease, an autoimmune disease, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, and chronic wounding skin disease (e.g., epidermolysis bullosa).
- cancer an inflammatory disease
- an autoimmune disease chronic fibrosis
- chronic obstructive pulmonary disease (COPD) chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- lung emphysema e.g., epidermolysis bullosa
- chronic wounding skin disease e.g., epidermolysis bullosa
- compositions and conjugates described herein are used for the prevention or treatment of cancer.
- Cancer generally includes any of various malignant neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites.
- Non-limiting examples of different types of cancer suitable for treatment using the conjugates or compositions of the present invention include ovarian cancer, breast cancer, lung cancer, bladder cancer, thyroid cancer, liver cancer, pleural cancer, pancreatic cancer, cervical cancer, prostate cancer, testicular cancer, colorectal cancer, colon cancer, anal cancer, bile duct cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, rectal cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, renal cancer (i.e., renal cell carcinoma), cancer of the central nervous system, skin cancer, oral squamous cell carcinoma, choriocarcinomas, head and neck cancers, bone cancer, osteogenic sarcomas, fibrosarcoma, neuroblastoma, glioma, melanoma, leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogen
- conjugates and compositions of the present invention can be co-administered with other therapeutic agents for the treatment of cancer.
- Suitable anti-cancer agents for combination therapy include, without limitation, cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, interferons, radiopharmaceuticals, peptides with anti-tumor activity such as TNF-a, pharmaceutically acceptable salts thereof; derivatives thereof, prodrugs thereof, and combinations thereof.
- a pharmaceutical composition comprising one or more conjugates of the present invention may be administered to a patient before, during, or after administration of an anticancer agent or combination of anti-cancer agents either before, during, or after chemotherapy.
- Treatment with the conjugate after chemotherapy may be particularly useful for reducing and/or preventing recurrence of the tumor or metastasis.
- the anti-cancer agent can be covalently linked directly or indirectly (e.g., via liposomes or nanoparticles) to a conjugate as described herein.
- Inflammatory diseases typically include diseases or disorders characterized or caused by inflammation. Inflammation can result from a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain that serves as a mechanism initiating the elimination of noxious agents and damaged tissue.
- the site of inflammation can include, for example, the lungs, the pleura, a tendon, a lymph node or gland, the uvula, the vagina, the brain, the spinal cord, nasal and pharyngeal mucous membranes, a muscle, the skin, bone or bony tissue, a joint, the urinary bladder, the retina, the cervix of the uterus, the canthus, the intestinal tract, the vertebrae, the rectum, the anus, a bursa, a follicle, and the like.
- inflammatory diseases suitable for treatment using the conjugates and compositions of the present invention include, but are not limited to, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), rheumatoid diseases such as rheumatoid arthritis, fibrositis, pelvic inflammatory disease, acne, psoriasis, actinomycosis, dysentery, biliary cirrhosis, Lyme disease, heat rash, Stevens-Johnson syndrome, mumps, pemphigus vulgaris, and blastomycosis.
- inflammatory bowel disease e.g., Crohn's disease or ulcerative colitis
- rheumatoid diseases such as rheumatoid arthritis, fibrositis, pelvic inflammatory disease, acne, psoriasis, actinomycosis, dysentery, biliary cirrhosis, Lyme disease, heat rash, Stevens-Johnson syndrome, m
- Autoimmune diseases generally include diseases or disorders resulting from an immune response against a self-tissue or tissue component such as, e.g., a self-antibody response or cell-mediated response.
- autoimmune diseases suitable for treatment using the conjugates and compositions of the present invention include, without limitation, organ-specific autoimmune diseases, in which an autoimmune response is directed against a single tissue, such as Type I diabetes mellitus, myasthenia gravis, vitiligo, Graves' disease, Hashimoto's disease, Addison's disease, autoimmune gastritis, and autoimmune hepatitis; and non-organ specific autoimmune diseases, in which an autoimmune response is directed against a component present in several or many organs throughout the body, such as systemic lupus erythematosus, progressive systemic sclerosis and variants, polymyositis, and dermatomyositis.
- Additional autoimmune diseases include, for example, pernicious anemia, primary biliary cirr
- conjugates and compositions of the present invention can be co-administered with other therapeutic agents for the treatment of inflammatory or autoimmune diseases.
- Suitable anti-inflammatory agents for combination therapy include, without limitation, corticosteroids, non-steroidal anti-inflammatory agents, antibodies such as infliximab, 5-aminosalicylates, antibiotics, pharmaceutically acceptable salts thereof; derivatives thereof, prodrugs thereof, and combinations thereof.
- Suitable immunosuppressive agents for combination therapy include, without limitation, azathioprine and metabolites thereof, anti-metabolites such as methotrexate, immunosuppressive antibodies, mizoribine monophosphate, cyclosporine, scoparone, FK-506 (tacrolimus), FK- 778, rapamycin (sirolimus), glatiramer acetate, mycopehnolate, pharmaceutically acceptable salts thereof, derivatives thereof, prodrugs thereof, and combinations thereof.
- the conjugates and compositions of the present invention are useful for treating an infection or infectious disease caused by, e.g., a virus, bacterium, fungus, parasite, or any other infectious agent.
- infectious diseases suitable for treatment include, but are not limited to, acquired immunodeficiency syndrome (AIDS/HIV) or HIV-related disorders, Alpers syndrome, anthrax, bovine spongiform encephalopathy (mad cow disease), chicken pox, cholera, conjunctivitis, Creutzfeldt-Jakob disease (CJD), dengue fever, Ebola, elephantiasis, encephalitis, fatal familial insomnia, Fifth's disease, Gerstmann-Straussler-Scheinker syndrome, hantavirus, helicobacter pylori, hepatitis (hepatitis A, hepatitis B, hepatitis C), herpes, influenza (e.g., avian influenza A (bird flu)),
- AIDS/HIV acquired immunode
- the conjugates and compositions of the present invention are useful for treating a neurological or musculoskeletal disorder.
- disorders include, but are not limited to, Alzheimer's disease, Aicardi syndrome, amnesia, amyotrophic lateral sclerosis (Lou Gehrig's Disease), anencephaly, aphasia, arachnoiditis, Arnold Chiari malformation, ataxia telangiectasia, Batten disease, Bell's palsy, brachial plexus injury, brain injury, brain tumor, Charcol-Marie-Tooth disease, encephalitis, epilepsy, essential tremor, Guillain-Barre Syndrome, hydrocephalus, hyperhidrosis, Krabbes disease, meningitis, Moebius syndrome, muscular dystrophy, multiple sclerosis, Parkinson's disease, peripheral neuropathy, postural or orthostatic tachycardia syndrome, progressive supranuclear palsy, Reye's syndrome, shingles, Sh
- the conjugates of the present invention typically have a therapeutic agent covalently or noncovalently attached to one or more of the peptide (e.g., comprising the amino acid sequence set forth in SEQ ID NO: l), one or more additional amino acid residues (e.g., lysine residues), or another moiety.
- the therapeutic agent is covalently or noncovalently attached to the peptide.
- the therapeutic agent is covalently or noncovalently attached to a PEG moiety.
- the therapeutic agent is cytotoxic.
- Suitable therapeutic agents provide beneficial, prophylactic, and/or therapeutic properties to a subject and include, but are not limited to, radionuclides, chemotherapeutic agents, nanoparticles, nanodroplets, liposomal drugs, and cytokines.
- therapeutic agents include, but are not limited to, radionuclides, chemotherapeutic agents, nanoparticles, nanodroplets, liposomal drugs, and cytokines.
- additional amino acids e.g., lysine
- moiety e.g., PEG moiety
- the therapeutic agent can be directly attached to the peptide or PEG portion of the conjugate via covalent attachment of the therapeutic agent to a primary amine group present in the peptide or PEG moiety.
- a therapeutic agent can also be bound to the peptide or PEG portion of the conjugate via noncovalent interactions (e.g., ionic bonds, hydrophobic interactions, hydrogen bonds, Van der Waals forces, dipole-dipole bonds, etc.).
- noncovalent interactions e.g., ionic bonds, hydrophobic interactions, hydrogen bonds, Van der Waals forces, dipole-dipole bonds, etc.
- the therapeutic agent is a cytotoxic chemotherapeutic agent.
- Cytotoxic chemotherapeutic agents are well known in the art and include anti-cancer agents such as alkylating agents (e.g., nitrogen mustards such as mechlorethamine (FIN2), cyclophosphamide, ifosfamide, melphalan (L-sarcolysin), and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa, alkyl sulphonates such as busulfan, nitrosoureas such as carmustine (BCNU), lomustine (CC LJ), semustine (methyl- CCN-U), and streptozoein (streptozotocin), and triazenes such as decarbazine (DTIC; dimethyltriazenoimidazolecarboxamide)), antimetabolites (e.g., folic acid
- the conjugate comprises (e.g., is covalently or noncovalently attached to) a therapeutic agent that is a pro-apoptotic peptide.
- a pro-apoptotic peptide can be D (KLAKLAK) 2 .
- the pro-apoptotic peptide is attached via a glycine linker to the peptide or a PEG moiety.
- the conjugate is linked to a particle that contains the therapeutic agent.
- Particles in this instance include, but are not limited to, nanoparticles and lipid-based vesicles such as liposomes or other similar structures composed of lipids.
- Nanoparticles can comprise PEG 5K CA 8 loaded with a chemotherapeutic agent (e.g., paclitaxel (PTX)).
- PTX paclitaxel
- Liposomes are typically spherical vesicles comprising a phospholipid bilayer that may be used as agents to deliver materials such as drugs or other compounds.
- Liposomes can be composed of naturally-derived phospholipids with mixed lipid chains (egg phosphatidylethanolamine) or of pure components like dioleolylphosphatidylethanolamine (DOPE).
- egg phosphatidylethanolamine mixed lipid chains
- DOPE dioleolylphosphatidylethanolamine
- the synthesis and use of liposomes is now well established in the art. Liposomes are generally created by sonication of phospholipids in a suitable medium such as water. Low shear rates create multilamellar liposomes having multi- layered structures. Continued high-shear sonication tends to form smaller unilamellar liposomes. Research has also been able to enable liposomes to avoid detection by the immune system, for example, by coating the liposomes with polyethylene glycol (PEG). It is also possible to incorporate species in liposomes, such as the peptide conjugates of the present invention, to help to target them to a
- nanoparticles as delivery agents for materials associated with or bound to the nanoparticles.
- Some types of nanoparticles comprise a core, often of metal and/or semiconductor atoms, to which one or more of the peptide or the first or second PEG moiety of the conjugate may be linked (see, e.g., PCT Publication Nos. WO 02/32404, WO 05/10816, and WO 05/1 16226).
- Other types of nanoparticles may be formed from materials such as liposomes.
- the nanoparticles may be quantum dots, e.g., nanocrystals of semiconducting materials which have chemical and physical properties that differ markedly from those of the bulk solid (see, e.g., Gleiter, Adv. Mater. , 4:474-481 (1992)). Now that their quantum size effects are understood, fundamental and applied research on these systems has become increasingly popular. An interesting application is the use of nanocrystals as luminescent labels for biological systems (see, e.g., Brucher et al , Science, 281 :2013-2016 (1998); Chan et al, Science, 281 :2016-2018 (1998); Mattousi et al, J. Am. Chem.
- Quantum dots have several advantages over conventional fluorescent dyes. For example, quantum dots emit light at a variety of precise wavelengths depending on their size and have long luminescent lifetimes.
- the therapeutic agent is a cytotoxic peptide or polypeptide capable of promoting cell death.
- Cytotoxic peptides and polypeptides are well known in the art and include, for example, ricin, abrin, Pseudomonas exotoxin, tissue factor, and the like. The use of ricin as a cytotoxic agent is described in Burrows et al , P.N.A.S. USA, 90:8996- 9000 (1993).
- tissue factor which leads to localized blood clotting and infarction of a tumor
- Ran et al Cancer Res., 58:4646-4653 (1998) and Huang et al, Science, 275 :547-550 (1997).
- Tsai et al Dis. Colon Rectum, 38: 1067-1074 (1995) describes the abrin A chain conjugated to a monoclonal antibody.
- Other ribosome-inactivating proteins are described as cytotoxic agents in PCT Publication No. WO 96/06641.
- Pseudomonas exotoxin may also be used as the cytotoxic polypeptide ⁇ see, e.g., Aiello et al , P.N.A.S. USA, 92: 10457-10461 (1995)).
- Certain cytokines, such as TNF-a and IL-2, may also be useful as cytotoxic and/or therapeutic agents.
- radioactive atoms may also be cytotoxic if delivered in sufficient doses.
- the therapeutic agent may comprise a radioactive atom which, in use, delivers a sufficient quantity of radioactivity to the target site so as to be cytotoxic.
- Suitable radioactive atoms for use in the peptide conjugates of the present invention include any of the radionuclides described herein, or any other isotope which emits enough energy to destroy a target cell, tumor, organ, or tissue.
- the isotopes and density of radioactive atoms in the conjugate are such that a dose of at least about 4000, 6000, 8000, or 10000 cGy is delivered to the target site and, preferably, to the cells at the target site and their organelles, particularly the nucleus.
- the radioactive atom may be attached to the conjugate in known ways.
- EDTA or another chelating agent may be attached to the peptide or PEG moiety and used to attach U 1 ln or 90 Y.
- tyrosine residues present in the peptide may be labeled with 125 I or 131 I.
- a benzoyl group is attached to the peptide or PEG moiety and used to attach 18 F.
- 4-[ 18 F]-fluorobenzoic acid can be used to radiolabel the peptide conjugates of the present invention.
- kits to facilitate and/or standardize the use of the conjugates of the present invention ⁇ e.g., comprising a peptide that comprises the amino acid sequence set forth in SEQ ID NO: l and a moiety) and compositions of the present invention (e.g., comprising conjugates of the present invention or a plurality thereof), as well as to facilitate the methods described herein.
- the kits comprise conjugates and/or compositions of the present invention. Materials and reagents to carry out these various methods can be provided in kits to facilitate execution of the methods.
- the term "kit” includes a combination of articles that facilitates a process, assay, analysis, or manipulation.
- kits comprising the conjugates or compositions of the present invention find utility in a wide range of applications including, for example, therapy (e.g., immunotherapy) and in vivo imaging (e.g., of a cell, tumor, organ, tissue, bioaggregate, biofilm, or the like).
- therapy e.g., immunotherapy
- in vivo imaging e.g., of a cell, tumor, organ, tissue, bioaggregate, biofilm, or the like.
- Kits can contain chemical reagents as well as other components.
- the kits of the present invention can include, without limitation, instructions to the kit user (e.g., directions for use of the conjugate or composition in immunotherapy, directions for use of the conjugate or composition in imaging a cell, tumor, organ, or tissue, etc.), apparatus and reagents for sample collection and/or purification, apparatus and reagents for product collection and/or purification, reagents for bacterial cell transformation, reagents for eukaryotic cell transfection, previously transformed or transfected host cells, sample tubes, holders, trays, racks, dishes, plates, solutions, buffers or other chemical reagents, suitable samples to be used for standardization, normalization, and/or control samples.
- Kits of the present invention can also be packaged for convenient storage and safe shipping, for example, in a box having a lid.
- Example 1 Rapid identification and development of a v P6-targeting conjugates as PET imaging agents using fluorescent cell-based on-bead sorting.
- This example describes a novel one-step on-bead screening approach using mixed fluorescent cells for the identification of conjugates comprising integrin a v p 6 -targeting peptides from a fluorobenzoyl OBOC peptide library (FIG. 1) and their subsequent development into 18F-peptides for noninvasive imaging via positron emission tomography (PET).
- the fluorescent cell lines DX3/ITGB6 mCherry and DX3 EmGFP employed in the on-bead screening were generated from the human melanoma DX3puroB6
- Integrin ⁇ ⁇ ⁇ 6 is a cell surface receptor is overexpressed in numerous aggressive cancers.
- the fluorobenzoyl peptide library which features the integrin a v p 6 -binding XXDLXXL motif as well as the fluorobenzoyl (FB) moiety for the development of 18F-peptides, was designed to 1) target the ⁇ ⁇ ⁇ 6 integrin and 2) eliminate post-screening modification of the identified peptides that can potentially cause loss of function and target specificity.
- the fluorobenzoyl peptide library was assembled with 1 gram of 90 ⁇ TentaGel resin using standard Fmoc-chemistry solid-phase peptide synthesis, starting with the coupling of Fmoc-Lys(alloc)-OH. Using the split-mix synthesis approach, the library was generated using 19 natural amino acids for the random position denoted by X in the XXDLXXLX motif. At the end of library synthesis, the alloc protecting group was removed and coupled with 4-fluorobenzoic acid (FBA) to make the fluorobenzoyl NH2- XXDLXXLXK(FB) peptide library.
- FBA 4-fluorobenzoic acid
- OBTC one-bead-two-color
- Peptides were confirmed to bind to ⁇ ⁇ ⁇ 6 integrin with subnanomolar affinity (IC 50 values ranging from 0.3 to 6.6 nM) with highest selectivity ratios of 10,000: 1 over ⁇ ⁇ ⁇ 5 , ⁇ ⁇ ⁇ 3 , and ⁇ ⁇ ⁇ and 500: 1 over ⁇ ⁇ ⁇ 8 integrin.
- the mixed fluorescent cell screening assay allowed one-step evaluation, allowing for expedited screening compared to other methods, of the OBOC library instead of multiple rounds of screening to identify target-specific peptide ligands.
- 4-fluorobenzoic acid incorporated to the side chain of C-terminal lysine for screening, it was assured that radiolabeling the identified peptides with [ 18 F]fluorobenzoic acid for in vitro studies would not hamper their binding profiles.
- a 9-mer XXDLXXLXK(FB) peptide library was assembled on TentaGel resin (lg, -3,000,000 beads) using standard Fmoc chemistry. Small aliquots (50 mg, -150,000 beads) were incubated with a mixture of red fluorescent DX3 ⁇ mCherry cells for 3 hours and evaluated under a fluorescent microscope. Beads that were covered only by red (i.e. a v p6-positive) cells were isolated; these beads were subsequently characterized by Edman sequencing. Following synthesis of the identified peptides, competitive binding ELISA was performed with purified integrin to evaluate binding specificities for the target ⁇ ⁇ ⁇ 6 integrin as well as closely related a v -integrins.
- DX3Puro (1) and DX3PuroP6 (2) have been described previously and were a generous gift from Dr. John Marshall.
- DX3Puro and DX3PuroP6 cells were transduced with lentivirus carrying EmGFP or mCherry (under control of an EFla promoter) and the blasticidin resistance gene (under control of a hybrid SV40/EM7 promoter).
- Transduced cells were cultured at ultra-low density in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS and blasticidin (10 ⁇ g/mL) at 37 °C in the presence of 5% C0 2 in air for 21 days.
- DMEM Dulbecco's Modified Eagle Medium
- FBS FBS
- blasticidin 10 ⁇ g/mL
- Clonal populations of DX3/EmGFP and DX3/ITGP6 mCherry were then isolated, expanded and screened for fluorescence and, in the case of DX3/ITGP6 mCherry, retention of ITGP6 expression.
- the coupling reaction was carried out at room temperature for 2 hours and Fmoc deprotection was achieved with 10 mL of a 20% v/v piperidine solution in DMF over 30 minutes. After the beads were thoroughly washed over the vacuum with multiple portions of DMF (3 x 10 mL each), methanol (MeOH) and DMF, they were split equally into 19 aliquots. A single Na- Fmoc-amino acid (3- fold excess, NovaBiochem) was added along with HATU (2.7 equivalents) and DIPEA (6 equivalents) to each aliquot. At the end of the coupling reaction, all aliquots were combined, mixed thoroughly, washed, and then redistributed into multiple aliquots for the next coupling step.
- DX3/ITGP6 mCherry and DX3/EmGFP cell lines were prepared from the human melanoma cell line DX3 as described above. As shown in FIGS. 2 A and 2B, equal populations of each cell line (total of 500,000 cells) were suspended in 10% fetal bovine serum (FBS) phenol red-free Dulbecco's Modified Eagle's Medium (DMEM; Gibco), added to a non-TC-treated culture dish (100 mm; Spectrum Chemicals and Laboratory Products), and then allowed to mix in the incubator at 37 °C for 1 hour prior to screening with the library beads.
- FBS fetal bovine serum
- DMEM Dulbecco's Modified Eagle's Medium
- the beads were added into the Petri dish containing mixed DX3/ITGP6 mCherry and DX3/EmGFP cells and incubated for 3 hours at 37 °C with gentle mixing. After incubation, the beads were analyzed under a fluorescent microscope. Beads that were >80% covered in DX3/ITGP6 mCherry cells (a v p6-specific) were manually selected with a micropipette. The positive beads isolated from the assay were sequenced using Edman degradation (FIGS. 3 and 4). Peptide sequences are disclosed in Table 1.
- Fmoc was removed with 20% piperidine solution, followed by thorough washes with DMF and MeOH prior to coupling of the next amino acid. The coupling cycle was repeated to extend the peptide chain, ending with a tert- butyloxycarbonyl (Boc)-protected amino acid at the N-terminus.
- Boc tert- butyloxycarbonyl
- ivDde-deprotection was achieved with 5 mL of freshly prepared 2% hydrazine in DMF for 30 minutes (2 x 15 minutes).
- 4-fluorobenzoic acid FBA, 3 equiv.
- Anti-a v capture antibody P2W7 (5 ⁇ g/mL, Novus Biologicals) was coated onto Nunc MaxiSorp 96-well plates, followed by blocking with BSA overnight at 4 °C. All wells were washed 3 times with PBS, followed by plating of purified integrin (3 ⁇ g/mL) and incubating at room temperature in a humid chamber for 1 hour. Peptide solutions, titrated (1 ⁇ -1 pM for ⁇ ⁇ ⁇ 6 integrin and 100 ⁇ -100 pM for ⁇ ⁇ ⁇ 3 integrin) and mixed with biotinylated natural ligand, were added to the integrin-coated wells in triplicate.
- Peptide ST 1-62 was radiolabeled with [ 18 F]fluorobenzoic acid on solid phase for cell binding studies (FIG. 6A).
- DX3purc 6 cell lines were used for this experiment.
- the radiolabeled peptide was formulated in PBS at 4 ⁇ /mL.
- Serum stability study analysis of Peptide 1 (ST1-62) (SEQ ID NO:2) was performed by first incubating the radiolabeled peptide ([ 18 F]; 25 ⁇ ) with commercially available mouse serum at 37 °C for an hour. The radiotracer was removed from serum by precipitating out the protein with cold EtOH and then injected into a UPLC for analysis. As expected for many Ti-peptides, this peptide was cleaved by proteases within an hour as shown in the UPLC trace. Results of serum stability assays are shown in FIGS. 7A and 7B.
- the ST 1-62 peptide was selected to move forward for radiolabeling with [ 18 F]fluorobenzoic acid for logP, serum stability, and cell binding studies.
- Log P -1.09 ⁇ 0.02 (FIG. 6B).
- Serum stability of the peptide was determined at 1 hour after incubating with mouse serum at 37 °C (FIG. 7 A).
- Flow cytometry was used to assay the binding of a peptide labeled with FAM-X (VGDLTYLKK-FAM-X; SEQ ID NO: 15) to DX3purop6 and DX3 puro cells.
- FAM-X VGDLTYLKK-FAM-X; SEQ ID NO: 15
- FIGS. 8A and 8B the peptide demonstrated increased binding to the a v p6-positive cells than the a v p 6 -negative cells at peptide concentrations of 10 ⁇ and 100 ⁇ .
- Lam et. al. A new type of synthetic library for identifying ligand-binding activity. Nature, 354 (7), 1991, 82-84.
- a conjugate comprising:
- conjugate of embodiment 4 wherein the one or more additional lysine residues are attached to the C-terminal end of the peptide and/or to one or more moieties. 6.
- imaging agent is selected from the group consisting of an FB group, a radionuclide, biotin, a fluorophore, a fluorescent protein, an antibody, horseradish peroxidase, alkaline phosphatase, and a combination thereof.
- conjugate of embodiment 20 further comprising an FB group that is attached to the N-terminal end of the peptide and a PEG 28 moiety that is attached to the C-terminal lysine residue, such that the conjugate comprises the sequence FB-VGDLTYLKK(FB)-PEG 2 8 (SEQ ID NO:3).
- conjugate of embodiment 19 wherein the conjugate comprises the sequence (VGDLTYLK-PEGi 2 ) 2 KK(FB) (SEQ ID NO:4), wherein the conjugate comprises a dimer of the amino acid sequence VGDLTYLK (SEQ ID NO: 1), wherein a PEG 12 moiety is attached to the C-terminal end of each member of the dimer, wherein both PEG 12 moieties are attached to the first of two additional lysine residues, and wherein an FB group is attached to the side chain of the second of the two additional lysine residues.
- composition comprising a conjugate of any one of embodiments 1 to 33 or a plurality thereof.
- composition of embodiment 34 wherein monodisperse PEG moieties having a defined chain length are present in the plurality of conjugates.
- composition of embodiment 36, wherein the multimeric conjugate is a dimer or a tetramer of the plurality of conjugates.
- kits for imaging or therapy comprising a conjugate of any one of embodiments 1 to 33 or a composition of any one of embodiments 34 to 38.
- the kit of embodiment 39 further comprising instructions for use.
- kit of embodiment 39 or 40 further comprising one or more reagents.
- a method for imaging a target tissue in a subject comprising:
- cancerous tissue is associated with pancreatic cancer, breast cancer, colorectal cancer, prostate cancer, or oral squamous cell carcinoma.
- MRI Magnetic Resonance Imaging
- MRS Magnetic Resonance Spectroscopy
- SPECT Single Photon Emission Computerized Tomography
- PET Positron Emission Tomography
- optical imaging any one of embodiments 42 to 48, wherein the conjugate is detected by Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), Single Photon Emission Computerized Tomography (SPECT), Positron Emission Tomography (PET), or optical imaging.
- MRS Magnetic Resonance Spectroscopy
- SPECT Single Photon Emission Computerized Tomography
- PET Positron Emission Tomography
- a method for preventing or treating an integrin-mediated disease or disorder in a subject comprising: administering to the subject a therapeutically effective amount of a conjugate of any one of embodiments 1 to 33 or a composition of any one of embodiments 34 to 38, wherein the conjugate comprises a therapeutic agent.
- any one of embodiments 53 to 55 wherein the disease or disorder is selected from the group consisting of cancer, an inflammatory disease, an autoimmune disease, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, radiation-induced pulmonary fibrosis, and chronic wounding skin disease.
- the disease or disorder is selected from the group consisting of cancer, an inflammatory disease, an autoimmune disease, chronic fibrosis, chronic obstructive pulmonary disease (COPD), lung emphysema, radiation-induced pulmonary fibrosis, and chronic wounding skin disease.
- COPD chronic obstructive pulmonary disease
- ⁇ ⁇ ⁇ 6 integrin-mediated disease or disorder is pancreatic cancer, breast cancer, colorectal cancer, prostate cancer, or oral squamous cell carcinoma.
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Abstract
Priority Applications (7)
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CN201780049057.2A CN109563135B (zh) | 2016-06-13 | 2017-06-13 | α(V)β(6)整合素结合肽及其使用方法 |
JP2019517203A JP7081832B2 (ja) | 2016-06-13 | 2017-06-13 | α(V)β(6)インテグリン結合ペプチドおよびその使用方法 |
CA3027364A CA3027364A1 (fr) | 2016-06-13 | 2017-06-13 | Peptides de liaison a l'integrine alpha (v) beta (6) et leurs procedes d'utilisation |
EP17813956.4A EP3468984A4 (fr) | 2016-06-13 | 2017-06-13 | Peptides de liaison à l'intégrine alpha (v) bêta (6) et leurs procédés d'utilisation |
AU2017283537A AU2017283537B2 (en) | 2016-06-13 | 2017-06-13 | Alpha(V)beta(6) integrin-binding peptides and methods of use thereof |
US16/217,397 US11185601B2 (en) | 2016-06-13 | 2018-12-12 | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
US17/504,072 US12023391B2 (en) | 2016-06-13 | 2021-10-18 | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
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EP (1) | EP3468984A4 (fr) |
JP (1) | JP7081832B2 (fr) |
CN (1) | CN109563135B (fr) |
AU (1) | AU2017283537B2 (fr) |
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Cited By (3)
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US11185601B2 (en) | 2016-06-13 | 2021-11-30 | The Regents Of The University Of California | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
US11591369B2 (en) | 2018-09-07 | 2023-02-28 | The Regents Of The University Of California | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
WO2024137442A1 (fr) | 2022-12-21 | 2024-06-27 | Gilead Sciences, Inc. | Polythérapie pour le traitement du cancer |
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JP6789823B2 (ja) * | 2014-04-15 | 2020-11-25 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 両末端peg化インテグリン結合性ペプチドおよびその使用方法 |
WO2021150614A1 (fr) * | 2020-01-21 | 2021-07-29 | Quantum-Si Incorporated | Composés et méthodes pour le marquage d'extrémité c sélectif |
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US5429133A (en) * | 1992-12-18 | 1995-07-04 | Neoprobe Corporation | Radiation responsive laparoscopic instrument |
DE10154180A1 (de) * | 2001-11-05 | 2003-05-15 | Basf Ag | gene die für genetische Stabilitäts-, genexpressions-und Faltungsproteine codieren |
EP1686114B1 (fr) | 2003-11-18 | 2009-10-07 | Mitsubishi Gas Chemical Company, Inc. | Procede de production de 2-alkylcysteine et procede de production de ses derives |
GB0520068D0 (en) * | 2005-10-03 | 2005-11-09 | Cancer Res Technology | av peptide ligand |
GB0718967D0 (en) * | 2007-09-28 | 2007-11-07 | Ge Healthcare Ltd | Peptide imaging agents |
JP6789823B2 (ja) * | 2014-04-15 | 2020-11-25 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 両末端peg化インテグリン結合性ペプチドおよびその使用方法 |
JP7081832B2 (ja) * | 2016-06-13 | 2022-06-07 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | α(V)β(6)インテグリン結合ペプチドおよびその使用方法 |
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2017
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- 2017-06-13 EP EP17813956.4A patent/EP3468984A4/fr active Pending
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- 2017-06-13 AU AU2017283537A patent/AU2017283537B2/en active Active
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11185601B2 (en) | 2016-06-13 | 2021-11-30 | The Regents Of The University Of California | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
US12023391B2 (en) | 2016-06-13 | 2024-07-02 | The Regents Of The University Of California | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
US11591369B2 (en) | 2018-09-07 | 2023-02-28 | The Regents Of The University Of California | Alpha(v)beta(6) integrin-binding peptides and methods of use thereof |
WO2024137442A1 (fr) | 2022-12-21 | 2024-06-27 | Gilead Sciences, Inc. | Polythérapie pour le traitement du cancer |
Also Published As
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US20220047730A1 (en) | 2022-02-17 |
CN109563135A (zh) | 2019-04-02 |
AU2017283537A1 (en) | 2019-01-03 |
WO2017218569A3 (fr) | 2018-02-01 |
AU2017283537B2 (en) | 2021-11-11 |
CA3027364A1 (fr) | 2017-12-21 |
JP7081832B2 (ja) | 2022-06-07 |
US20190328910A1 (en) | 2019-10-31 |
EP3468984A4 (fr) | 2020-03-11 |
JP2019524871A (ja) | 2019-09-05 |
CN109563135B (zh) | 2024-01-23 |
EP3468984A2 (fr) | 2019-04-17 |
US12023391B2 (en) | 2024-07-02 |
US11185601B2 (en) | 2021-11-30 |
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